The direction and hypotheses of Project 1 emerge from key findings that the decreases in growth hormone and IGF-1 are critical factors in the age-related decline in vascular density, cerebral blood flow, glucose metabolism and impaired performance in hippocampally-dependent tasks of learning and memory. These findings have led us to propose that decreases in vascular density and angiogenesis, pertubations in vascular reactivity, and impairments in vascular transport and secretion of key trophic factors contribute to a mismatch between regional metabolic demand and blood flow in aged animals: The resulting alterations within the vascular-glia-neuronal micro-environment impair cellular proliferation, synaptic efficacy and performance on hippocampally-dependent tasks of learning and memory. The following aims are proposed:1) Assess whether growth hormone/IGF-1 deficiency contributes to a regional reduction in capillary and arteriolar density, angiogenesis, and blood flow. 2) Assess whether alterations in cerebral vascular reactivity occur with age (the unique relationship between Em, [Ca2+]i and vessel diameter);the effects of aging on SR Ca2+ release events in the cerebral circulation and the mechanisms by which growth hormone and IGF-1 replacement therapy reverse the age-associated alterations in cerebral vascular reactivity. 3) Determine whether trophic factors produced by the vasculature and found to be necessary for hippocampally-dependent processes of learning and memory are reduced in the hippocampal microenvironment of aged animals and whether administration of growth hormone results in increased levels of these trophic factors and improved cognitive performance. These studies will use young and old animals and old animals treated with growth hormone that restores cognitive function and the unique model of adultonset growth hormone and IGF-1 deficiency developed by the Animal Core to assess the effects of a primary, specific deficiency of these hormones apart from aging. The results of these studies will greatly extend our understanding of the role of growth hormone and IGF-1 in regulation of vascular structure and function and the inter-relationships that occur between cerebrovasculature dysfunction and functional changes in the brain that are precursors to age-related disease, cognitive dysfunction and increased risk of dementia.